Biomarker investigations from the ATAC trial: the role of TA01

cDNA arrays and proteomic analyses have allowed the rapid identification of specific genes and proteins implicated in multiple tumor types. These molecules must then be validated as clinically relevant prognostic and predictive markers, and this translational research is best conducted in the context of clinical trials. Outcomes data and clinical specimens collected in the ‘Arimidex’, Tamoxifen, Alone or in Combination (ATAC) study, for example, can now be used to compare the expression of biomarkers with clinical outcomes. In this study, adjuvant tamoxifen and anastrozole (‘Arimidex’) were compared alone and in combination in more than 9000 women with breast cancer. Anastrozole was found to be superior to tamoxifen in terms of disease-free survival, time to recurrence, and reduction in the incidence of contralateral tumors. Importantly, tissue specimens from surgical excision, local relapse, and contralateral breast cancer were collected and paraffin-embedded for storage. In the TA01 (TransATAC) program, these specimens will be studied (after obtaining patient consent) using tissue microarrays; tissue biopsy cores 0.6 mm in diameter will be removed from donor blocks and placed on recipient blocks, which will be sectioned to allow the simultaneous analysis of the same samples for multiple biomarkers. These analyses can help determine differential benefits of treatment with anastrozole or tamoxifen, depending on the expression of particular biomarkers in tumor cells. This research also should clarify de novo and acquired resistance mechanisms, and the validation of relevant molecular pathways could guide the development of new drugs. Ultimately, the TA01 program has the potential to favorably impact treatment choices for breast cancer. This revised version was published online in August 2006 with corrections to the Cover Date.     

GENETIC DELETION OF DETOXIFIC ENZYME GSTM1 AND GSTTI AS A HOST SUSCEPTIBLE FACTOR FOR NASOPHARYNGEAL CARCINOMA

Objective: To study the gene polymorphisms of GSTT1 and GSTM1 in nasopharyngeal carcinoma (NPC) patients and controls in an incidental area to evaluate the relationship between specific genotype and genotype combinations of these polymorphisms with the risk of NPC. Methods: Cases and controls all came from the Southwestern Guangxi. DNAs were extracted from their WBC. PCR technique was used to calculate the deletion rate of the two detoxific enzyme genes. Results: In this high risk area of NPC, the residents had high level deletion rates of 47.4% (64/135) Ml and T1 40.7% (55/135). The deletion rates were even higher in NPC patients, 61.5% (56/91) for Ml and 59.3% (54/91) for T1 respectively. There were statistical significances compared with control,P<0.05 andP<0.01 for Ml and T1 respectively. The difference was more significant in terms of combined Ml and T1 deletion between patients and controlsx ²=12.533,P=0.002. Conclusion: The combined deletion of detoxific enzyme genes GSTM1 and GSTT1 may be an important genetic susceptible factor for NPC in Guangxi. Biography: DENG Zhuo-lin (1929-), male, professor of pathology, Guangxi Medical University, majors in tumor pathology. E-mail :zhuolin@hotmail.com     

Expression profiling of T-cell lymphomas differentiates peripheral and lymphoblastic lymphomas and defines survival related genes.

PURPOSE: T-Cell lymphomas constitute heterogeneous and aggressive tumors in which pathogenic alterations remain largely unknown. Expression profiling has demonstrated to be a useful tool for molecular classification of tumors. EXPERIMENTAL DESIGN: Using DNA microarrays (CNIO-OncoChip) containing 6386 cancer-related genes, we established the expression profiling of T-cell lymphomas and compared them to normal lymphocytes and lymph nodes. RESULTS: We found significant differences between the peripheral and lymphoblastic T-cell lymphomas, which include a deregulation of nuclear factor-kappaB signaling pathway. We also identify differentially expressed genes between peripheral T-cell lymphoma tumors and normal T lymphocytes or reactive lymph nodes, which could represent candidate tumor markers of these lymphomas. Additionally, a close relationship between genes associated to survival and those that differentiate among the stages of disease and responses to therapy was found. CONCLUSIONS: Our results reflect the value of gene expression profiling to gain insight about the molecular alterations involved in the pathogenesis of T-cell lymphomas.     

Lanzoprazole promotes gastric carcinogenesis in rats with duodenogastric reflux

Background Duodenogastric reflux is known to cause an increased frequency of cancer in the glandular portion of the stomach in rats. Furthermore, it is debated whether inhibition of gastric acid secretion may promote gastric carcinogenesis. In the present study we examined the combined effect of gastroduodenal reflux and acid inhibition with respect to the development of gastric carcinoma in the rat.Methods Following the construction of a gastrojejunostomy in male Wistar rats, half of them were given the proton pump inhibitor lanzoprazole for 1 year. The rats were then killed and the pH in the stomach and gastrin in blood were measured. The stomach was examined macroscopically as well as histologically.Results Gastrin levels at autopsy were significantly increased in treated rats compared to the control group, confirming an effect of lanzoprazole on gastric acid secretion. Body weight was significantly reduced in the treated rats. Thirty of 79 rats developed gastric cancer, and they were all adenocarcinomas of the Lauren intestinal type. Gastric cancers occurred significantly more often in lanzoprazole-treated rats (50%) compared with controls (27%).Conclusion Lanzoprazole given orally enhances the carcinogenic effect of duodenogastric reflux in rats.     

The endoscopic evaluation of gastritis,gastric remnant residue,and the incidence of secondary cancer after pylorus-preserving and transverse gastrectomies

Background Pylorus-preserving gastrectomy (PPG) and transverse gastrectomy (TrG) have been accepted as function-preserving procedures for node-negative early gastric cancer. It is believed that a better quality of life is guaranteed after PPG or TrG compared to that after distal subtotal gastrectomy (DSG) with Billroth type-I reconstruction. However, objective evaluations of the gastric remnant following gastrectomy have not been widely reported, and the real advantages and disadvantages of PPG or TrG over DSG remain unclear. Moreover, the risk of secondary cancer after PPG or TrG is uncertain.Methods Between 1991 and 2000, 834 DSGs were carried out in our institute for preoperatively diagnosed patients with early gastric cancer. The degree of residual gastritis and the amount of diet residue in the gastric remnant were evaluated by annual gastrointestinal endoscopic investigations prospectively for 72 patients after PPG, 95 patients after TrG, and 60 patients after DSG. These analyses were performed using the RGB classification (residue, gastritis, bile). The incidence of disease greater than or equal to grade 2 was calculated, and the time trends of the incidence for each procedure were also studied for 3 years after gastrectomy. In addition, secondary cancer cases in the gastric remnant mucosa were checked for each procedure during this period, and the incidence of secondary cancer after each operation was calculated.Results The incidence of gastritis, of grade 2 or more, found in the gastric remnant was significantly lower after PPG (1.4%) and TrG (2.1%) than after DSG (43.3%). However, the incidence of moderate or greater residue in the gastric remnant, grade 2 or more, was significantly higher after PPG (45.8%) and TrG (40.0%) than after DSG (11.7%). The analysis of time trends of gastritis and diet residue reflected the significant advantage or disadvantage for each procedure 1 year after surgery. The analysis also included these factors without consideration of elapsed time following surgery. Two patients after PPG (2.8%) and three patients after TrG (3.2%) developed secondary cancer in the gastric remnant. No DSG-treated patient showed new cancer genesis in the remaining stomach.Conclusion PPG and TrG have the advantage over DSG in preventing postoperative gastritis in the gastric remnant. On the other hand, moderate or greater diet residue in the gastric remnant is more common after PPG or TrG than after DSG. For the risk of carcinogenesis in the remnant gastric mucosa, we could not conclude that there was any apparent difference between these range-limited gastrectomies and conventional DSG. Further study is necessary to determine the significant advantages and disadvantages of using PPG or TrG.     

Efficiency of adjuvant immunochemotherapy following curative resection in patients with locally advanced gastric cancer

Background Despite curative resection, 50%–90% of gastric cancer patients die of disease relapse. Although some clinical trials have indicated that chemotherapy and immunochemotherapy may be effective modalities, more recent studies have not been able to define the standard treatment for advanced gastric cancer. The present study evaluated the effect of adjuvant immunochemotherapy with the use of BCG (bacille Calmette-Guérin) and FAM (5-fluorouracil, adriamycin, mitomycin C) chemotherapy on the survival of patients with locally advanced resectable gastric cancer.Methods A total of 156 patients with stage III or IV gastric cancer who had undergone curative resection were randomly assigned to three treatment groups: BCG + FAM (immunochemotherapy), FAM (chemotherapy), and control (surgery only). Treatment was continued for 2 years or until death. Further postsurgical follow up was carried on for up to 10 years.Results Overall 10-year survival was 47.1% for the immunochemotherapy group (P < 0.037 vs FAM and P < 0.0006 vs control), 30% for the chemotherapy group (vs control, NS), and 15.2% for the control group. In patients with pT2/T3 primary tumors, 10-year survival was 55.3% for BCG + FAM vs 28.2% for FAM (P < 0.01) and 14.6% for the control group (P < 0.00018). BCG + FAM signifi-cantly improved the survival of patients with intestinal-type but not diffuse-type cancer. Immunochemotherapy was well tolerated.Conclusion This study, based on a limited number of patients, indicates that adjuvant immunochemotherapy (BCG + FAM) may prolong the survival of gastric cancer patients after curative gastrectomy; in particular, in patients with pT2/T3 tumors and intestinal-type primary tumors. There was no survival benefit from FAM adjuvant chemotherapy.     

In vitro evaluation study of the membrane autotransfusion system experimental prototype: MATS-I

Abstract: Membrane Autotransfusion System (MATS) utilizing plasmapheresis technology has been developed in our laboratory. A specially designed polyethylene hollow fiber membrane was utilized. This study was conducted to evaluate performance of the first experimental prototype, MATS-I. The results of this study showed that the MATS-I could concentrate diluted blood at 10% of the initial hematocrit concentration (HCTi) into over 40% after passing through the system at a transmembrane pressure of 70 mm Hg. Moreover, the MATS-I can continuously treat 10,000 ml of diluted blood at various HCTi levels without deteriorating its performances. Even though the MATS-I met all required performances as an autotransfusion system, several areas of improvement of the system were necessary to meet various clinical needs. The next prototype, MATS-II, can be designed based on experiences obtained from the MATS-I. The MATS is smaller, more atraumatic and continuous, and is a faster system when compared to the currently available centrifugal autotransfusion devices.